As with other pharmaceutical products, it is desirable to attain improvements with respect to opioid product safety. In particular, there is a continuing need in the art to provide improved processes for making high quality, synthetic or partially synthetic opioid compounds.
Opioids are among the world's oldest known drugs as the therapeutic use of the opium poppy predates recorded history. The term “opioid” refers to both opiates (i.e., natural alkaloids found in the resin of the opium poppy) and synthetic substances, and is typically defined as any psychoactive chemical that resembles morphine or other opiates in its pharmacological effects. Opioids function by binding to opioid receptors found principally in the central and peripheral nervous system and the gastrointestinal tract and the receptors in these organ systems mediate both the beneficial effects and the side effects of opioids. The analgesic (painkiller) effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance. The side effects of opioids include sedation, respiratory depression, constipation, and a strong sense of euphoria.
Two opiates, oripavine (Formula Ia) and thebaine (Formula Ib), are widely used in opiate chemistry to produce 14-hydroxymorphinone and 14-hydroxycodeinone compounds that are intermediate compounds in the production of oxymorphone and oxycodone drug substances. In addition to being intermediate compounds, 14-hydroxymorphinone and 14-hydroxycodeinone are also considered to be impurities as they are α,β-unsaturated ketone (commonly referred to as “ABUK”) compounds that are often found in the production of oxymorphone and oxycodone as well as their salts. According to the U.S. Food and Drug Administration (“FDA”), ABUKs have been demonstrated to be reactive with DNA, resulting in genotoxicity. Potentially genoxic compounds present a safety concern because the compounds pose a cancer risk.
In 2002, FDA determined that the active pharmaceutical ingredient (“API”) of oxycodone opioid drug product included the ABUK impurity, 14-hydroxycodeinone. Through review of in vitro genetic toxicology studies, FDA concluded that 14-hydroxycodeinone tested positive in the in vitro chromosome aberration assay, posed a potential safety concern, and therefore required further safety qualification or reduction to not more than (“NMT”) 0.001% in the API. See FDA response to citizen petition and petition for stay of action filed by Purdue Pharma L.P. and Rhodes Technologies Inc. (issued Mar. 24, 2008). Subsequently, FDA determined that all the thebaine-derived opioid products, including oxymorphone products, might contain one or more ABUK impurities. FDA added that, in addition to 14-hydroxycodeinone, 14-hydroxymorphinone is a process impurity in some synthetic pathways leading to oxymorphone. As a result, FDA now requires that both of these ABUK impurities be reduced to appropriate levels (e.g., ≤0.001% or 10 ppm) in drug products.
Oripavine and thebaine are relatively easily converted to 14-hydroxymorphinone and 14-hydroxycodeinone compounds by oxidation with, for example, peroxyacids including those formed by reacting carboxylic acid and hydrogen peroxide. Peroxyacid oxidation of oripavine and thebaine to make 14-hydroxymorphinone and 14-hydroxycodeinone compounds has become a widely accepted procedure for large scale production of oxymorphone and oxycodone as well as their salts.

However, during the oxidation of oripavine and thebaine to 14-hydroxymorphinone and 14-hydroxycodeinone compounds, several by-products are formed, including 8,14-dihydroxy-7,8-dihydromorphinone and 8,14-dihydroxy-7,8-dihydrocodeinone. Thus, for example, during the oxidation of thebaine to produce 14-hydroxycodeinone, the 8,14-dihydroxy-7,8-dihydrocodeinone (Formula III) by-product is produced as an impurity. In the subsequent production of oxycodone free base from 14-hydroxycodeinone (IIb), the 8,14-dihydroxy-7,8-dihydrocodeinone impurity can be carried through the process and become part of the isolated oxycodone free base composition.
Also, during the conversion of oxycodone free base to an oxycodone salt (e.g., oxycodone hydrochloride), the 8,14-dihydroxy-7,8-dihydrocodeinone impurity can convert back into 14-hydroxycodeinone (IIb) under acidic conditions. In fact, Chapman et al (U.S. Pat. No. 7,683,072) note that during the production of oxycodone free base from 14-hydroxycodeinone by hydrogenation the isomeric impurity 8,14-dihydroxy-7,8-dihydrocodeinone is carried through the process and “during conversion of oxycodone free base to oxycodone hydrochloride, the impurity undergoes acid-catalyzed dehydration and is converted into 14-hydroxycodeinone.” A similar conversion is expected to take place in making oxymorphone from oripavine. Thus, a process that effectively controls and or minimizes the amount of 8,14-dihydroxy impurities, which are now known to be capable of converting to ABUKs, can therefore be highly beneficial in the production of the oxymorphone and oxycodone opiates including their salts.

Two isomers of 8,14-dihydroxy-7,8-dihydrocodeinone, with the 8α and 8β stereochemistry, are possible and recent publications, including the Chapman '072 patent and a Baldwin Declaration filed in support thereof, indicate that the 8α-isomer is hydrolytically more unstable than the 8β-isomer such that it more easily converts to 14-hydroxycodeinone. While the preparation and characterization of 8β,14-dihydroxy-7,8-dihydrocodeinone is known in the chemical literature, the preparation, isolation and characterization of 8α,14-dihydroxy-7,8-dihydrocodeinone is not as well understood. Keskeny et al (WO 2012/003468 A1) have reported an analytical methodology to quantify the isomers of 8,14-dihydroxy-7,8-dihydrocodeinone by LC/MS (SIM) in which two HPLC peaks are identified having a mass corresponding to 8,14-dihydroxy-7,8-dihydrocodeinone, one of which was confirmed as the 8β-isomer (β-diol) (RRT 0.91 relative to oxycodone) while the second peak was assigned as the 8α-isomer (RRT 0.82 relative to oxycodone). The peak at RRT 0.82 is more appropriately referred to throughout this disclosure as the “β-diol isomer” since it has not been isolated and characterized, and thus its structure has not yet been unequivocally proven.
The Keskeny '468 application also reports that the level of the β-diol isomer can be present in up to 1000 ppm level and that the β-diol can be present at even higher levels in oxycodone free base. Thus, at these impurity levels, the potential for oxycodone products having unacceptably high levels of the 14-hydroxycodeinone (ABUK) impurity exists. This is also true for oxymorphone products. Accordingly, a need exists in the art for improving the processes for making oxycodone and oxymorphone products such that they contain acceptably low levels (ppm levels) of ABUK impurities.
All references cited herein are incorporated by reference in their entireties for all purposes.